Prognostic roles of tetrahydroxy bile acids in infantile intrahepatic cholestasis

Chee-Seng Lee,Akihiko Kimura,Jia-Feng Wu,Yen-Hsuan Ni,Hong-Yuan Hsu,Mei-Hwei Chang,Hiroshi Nittono,Huey-Ling Chen

doi:10.1194/jlr.p070425

Abstract

Tetrahydroxy bile acids (THBAs) are hydrophilic and are present at minimal or undetectable levels in healthy human adults, but are present at high levels in bile salt export pump (abcb11)-knockout mice. The roles of THBAs in human cholestatic diseases are unclear. We aimed to investigate the presence of THBAs in patients with infantile intrahepatic cholestasis and its correlation with outcome. Urinary bile acids (BAs) were analyzed by GC-MS. Data were compared between good (n = 21) (disease-free before 1 year old) and poor prognosis groups (n = 19). Good prognosis patients had a higher urinary THBA proportion than poor prognosis patients [25.89% (3.45-76.73%) vs. 1.93% (0.05-48.90%)]. A urinary THBA proportion >7.23% predicted good prognosis with high sensitivity (95.24%), specificity (84.21%), and area under the curve (0.91) (P < 0.0001). A THBA proportion 7.23% was an independent factor for decreased transplant-free survival (hazard ratio = 7.16, confidence interval: 1.24-41.31, P = 0.028). Patients with a confirmed ABCB11 or tight junction protein 2 gene mutation (n = 7) had a minimally detectable THBA proportion (0.23-2.99% of total BAs). Three patients with an ATP8B1 mutation had an elevated THBA proportion (7.51-37.26%). In conclusion, in addition to disease entity as a major determinant of outcome, a high THBA level was associated with good outcome in the infantile intrahepatic cholestasis patients.

Highlights

Tetrahydroxy bile acids (THBAs) are hydrophilic and are present at minimal or undetectable levels in healthy human adults, but are present at high levels in bile salt export pump-knockout mice
Relationship of urinary BA profile with patient outcome To investigate whether the BA profile can be used as a marker for predicting patient outcome, we analyzed urine samples collected from 40 patients before 1 year of age because BA composition has been shown to differ among patients of different ages [18]
Two patients were confirmed with ABCB11 mutation, one patient with ATP8B1 mutation, two patients with tight junction protein 2 (TJP2) mutation, and four patients with inborn errors of BA metabolism (IEBAM)

Summary

Introduction

Tetrahydroxy bile acids (THBAs) are hydrophilic and are present at minimal or undetectable levels in healthy human adults, but are present at high levels in bile salt export pump (abcb11)-knockout mice. Good prognosis patients had a higher urinary THBA proportion than poor prognosis patients [25.89% (3.45–76.73%) vs 1.93% (0.05–48.90%)]. A urinary THBA proportion >7.23% predicted good prognosis with high sensitivity (95.24%), specificity (84.21%), and area under the curve (0.91) (P < 0.0001). Patients with a confirmed ABCB11 or tight junction protein 2 gene mutation (n = 7) had a minimally detectable THBA proportion (0.23–2.99% of total BAs). In addition to disease entity as a major determinant of outcome, a high THBA level was associated with good outcome in the infantile intrahepatic cholestasis patients.—Lee, C-S., A. The BA profile and BA metabolism are altered in cholestasis patients [4], resulting in the accumulation of high concentrations of BAs with cytotoxic effects, leading to severe liver injury or even death.

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